Minkeviciene R, Ihalainen J, Malm T, Matilainen O, Keksa-Goldsteine V, Goldsteins G, Iivonen H, Leguit N, Glennon J, Koistinaho J, Banerjee P, Tanila H
A.I.Virtanen Institute for Molecular Sciences, University of Kuopio, Finland.
J Neurochem. 2008 May;105(3):584-94. doi: 10.1111/j.1471-4159.2007.05147.x. Epub 2007 Nov 26.
We assessed baseline and KCl-stimulated glutamate release by using microdialysis in freely moving young adult (7 months) and middle-aged (17 months) transgenic mice carrying mutated human amyloid precursor protein and presenilin genes (APdE9 mice) and their wild-type littermates. In addition, we assessed the age-related development of amyloid pathology and spatial memory impaired in the water maze and changes in glutamate transporters. APdE9 mice showed gradual spatial memory impairment between 6 and 15 months of age. The stimulated glutamate release declined very robustly in 17-month-old APdE9 mice as compared to 7-month-old APdE9 mice. This age-dependent decrease in stimulated glutamate release was also evident in wild-type mice, although it was not as robust as in APdE9 mice. When compared to individual baselines, all aged wild-type mice showed 25% or greater increase in glutamate release upon KCl stimulation, but none of the aged APdE9 mice. There was an age-dependent decline in VGLUT1 levels, but not in the levels of VGLUT2, GLT-1 or synaptophysin. Astrocyte activation as measured by glial acidic fibrillary protein was increased in middle-aged APdE9 mice. Blunted pre-synaptic glutamate response may contribute to memory deficit in middle-aged APdE9 mice.
我们通过微透析技术，对携带突变型人类淀粉样前体蛋白和早老素基因的成年幼龄（7个月）和中年（17个月）转基因小鼠（APdE9小鼠）及其野生型同窝小鼠在自由活动状态下的基线和氯化钾刺激后的谷氨酸释放情况进行了评估。此外，我们还评估了淀粉样病理的年龄相关性发展、水迷宫中空间记忆的受损情况以及谷氨酸转运体的变化。APdE9小鼠在6至15个月大时表现出逐渐的空间记忆损害。与7个月大的APdE9小鼠相比，17个月大的APdE9小鼠中，刺激后的谷氨酸释放显著下降。尽管野生型小鼠中这种刺激后谷氨酸释放的年龄依赖性下降不如APdE9小鼠明显，但同样很显著。与各自的基线相比，所有老年野生型小鼠在氯化钾刺激后谷氨酸释放增加了25%或更多，但老年APdE9小鼠均未出现这种情况。VGLUT1水平呈现年龄依赖性下降，但VGLUT2、GLT-1或突触素的水平没有下降。通过胶质酸性纤维蛋白测量的星形胶质细胞活化在中年APdE9小鼠中增加。突触前谷氨酸反应减弱可能导致中年APdE9小鼠出现记忆缺陷。
